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Dave Lockwood (Jason Bateman) and Mitch Planko (Ryan Reynolds) are close friends who are each jealous of the other's lifestyle. While Dave is a lawyer with a wife and kids, Mitch is a freewheeling actor who has sex with many different women. After getting drunk at a bar, Mitch and Dave urinate in a park's fountain, and simultaneously wish that they had each other's lives.

The next morning, Mitch and Dave realize they have switched bodies. Mitch remembers the wish they made the night before and they drive back to the park, planning to urinate again in the fountain and wish for their original lives back, but find the fountain has been removed for restorations. Forced to wait a few days until the parks department can locate the fountain, Mitch and Dave agree to pretend to be each other for the day. When Mitch arrives at Dave's law firm office, he befriends Dave's attractive assistant, Sabrina McArdle (Olivia Wilde). However, Mitch's lack of professionalism and legal knowledge cause a big merger to fall through. Meanwhile, Dave arrives at Mitch's film shoot to discover that it is a porno.

Tired of pretending to be Mitch, Dave has them go back to his house to tell his wife Jamie (Leslie Mann) the truth, but Jamie does not believe him. Dave gives Mitch advice on how to behave professionally and Mitch sets Dave up on a date with Sabrina, who Dave has had a crush on.

After speaking with his father, Mitch rededicates himself to doing everything Dave's life demands, from taking care of the kids and buying groceries to making decisions at the firm. On the night of her ballet recital, Cara is about to be pushed by the other girl again, but takes Mitch's advice and throws her to the floor, to which Mitch foul-mouthedly cheers. Cara tells Dave that she loves him and Mitch says the same thing, but feels guilty for doing so immediately after. That night, Mitch and Jamie begin to have sex with each other, but Mitch angrily finds that his guilt will not allow him to become erect, and he admits that he is not cut out for the responsibilities of an adult. Jamie comforts him, and he discreetly rests his head on her breasts.

The next day, Dave decides to take advantage of being Mitch and takes the day off. Dave does everything that he finds relaxing, including going to an Aquarium and watching a showing of National Lampoon's Animal House at the theater. After Dave finishes having fun, he calls Mitch to help show him how to act fun on his date with Sabrina that night. Mitch teaches Dave how to act like him, and finally shaves off Dave's pubic hair. Sabrina comes to meet him at a classy restaurant and, despite only originally going because Mitch told her to, they eventually legitimately start liking each other, and get tattoos. Dave walks Sabrina home, and she tells him to call her. Later, Jamie asks "Dave" about their anniversary party and he asks why Mitch was not invited. She says that he told her not to invite him because he was afraid Mitch would ruin it with his usual antics. Meanwhile, Dave is rollerblading through the park when he is called by the woman from the District Manager's office and tells him that they found where the statue was moved to. Dave goes to meet Mitch and tell him, but when Dave gets there, he and Mitch imply that they want to stay each other and Dave leaves. However, Mitch forgets about the Dialogue Night that he and Jamie had planned and accidentally stands her up.

The following day, Mitch goes with the rest of the representatives to the new merger meeting between the two firms. The Japanese representatives only offer $625 million to merge, $75 million short of their hoped for $700 million. They are about to agree when Mitch says that he has noticed the firm's representatives have not started leaving, which means they are still willing to up the price, comparing the whole situation to sex and porn. He tells the moderator to tell the firm they demand $725 million and has Dave's firm's representatives begin to leave. They successfully scare the other firm into agreeing and celebrate. Mitch and Dave's family go to a gala being held by Dave's firm in honor of Dave being made partner, but Jamie is still upset over how she knows Dave will still never truly be happy. Meanwhile, Dave and Sabrina are at a baseball game when a thunderstorm suddenly hits, and they decide to go to Mitch's house to wait it out. Sabrina tells Dave that she is going to have sex with him, and takes off her pants and bra, but when they begin, he notices a tattoo of a many spotted skipperling on her hip, the same type of butterfly his daughter said was her favorite, and regretfully leaves, saying he wants to go home. Back at the gala, Steel is giving his speech about the amazing accomplishments Dave made over the years, and how the only thing he loves more than the law is his family. Mitch says to himself that he did not earn the title he is getting, as Dave quickly drives up to the gala, rushes in, and kisses Jamie, finally letting her know that he is who he said he was. He tells her that he loves her, and he and Mitch drive to the Peachtree Galleria, where the fountain was moved. They run in, planning to urinate in the fountain, but find it located in the center of the Galleria, where it is surrounded by hoards of people walking by. They decide to not wait and do it then, but Mitch finds that he is too embarrassed to urinate, especially after the crowd notices Dave doing so. Mitch asks why Dave did not invite him to his anniversary party, and Dave admits that he was embarrassed of him, but has grown to respect him while he was in his body and this allows Mitch to relax enough to be able to urinate. Mitch and Dave try wishing for their original lives back, but it does not work. Security begins to come to arrest them, but on the third try the Galleria's lights go out, and they both run away before they turn back on. The confused crowd looks around, and the camera pans up to the face of the statue, once again smiling.

In the epilogue, Dave is awoken by his babies crying that night, thrilled to realize that he has finally returned in his original body. Dave continually kisses Jamie and happily goes to change the babies. At his home, Mitch awakens to enthusiastically admire himself and happily get breakfast with Sabrina, not realizing that the tattoo Dave got is a picture of his face on Mitch's back with the caption "I ♥ Dave". Mitch goes and speaks at his father's wedding and later attends Dave's anniversary a month later. In the post-credits scene, Dave and Jamie get high then go to the Aquarium Dave went to earlier, while Mitch and Sabrina have sex for the first time and Mitch sends Dave the porno film he starred in.

The film was shot in Atlanta, Georgia from October 2010 to January 2011, which is also its setting. There were open castings at Turner Field and other venues in Atlanta. Several of the bar scenes were shot on location at a bar called Joe's on Juniper, in midtown Atlanta. The exterior and interior scenes of the Lockwood home were shot on location at a Buckhead residence designed by Atlanta residential designer Steve McClanahan. The movie was also shot in Los Angeles. The house used for the Lockwood home is on the 2400 block of Gramercy Park in historic West Adams. Despite being set in the summertime, production continued during a major winter storm that briefly crippled the city in January, leaving Peachtree and other streets covered in snow and ice and nearly preventing the governor's inauguration. Reynolds complimented the city in his interview on The Tonight Show with Jay Leno, but joked that he thought the city "was trying to kill" him because of several unrelated incidents on the set and in his personal life that happened to occur during production.[10] During her interview on Jimmy Kimmel Live!, Olivia Wilde stated that she refused to appear naked or take most of her clothes off and used a body double for some shots and wore pasties for close-up and upper shots. Leslie Mann has also followed this technique while other actresses used prosthetics.

The Change-Up received mostly negative reviews. On Rotten Tomatoes, the film holds a rating of 25%, based on 147 reviews, with a rating average of 4.4/10. The site's consensus reads, "There's a certain amount of fun to be had from watching Bateman and Reynolds play against type, but it isn't enough to carry The Change-Up through its crude humor and formulaic plot."[11] On Metacritic, the film has a score of 39 out of 100, based on 35 critics, indicating "generally unfavorable reviews".[12]

British newspaper The Telegraph named The Change-Up one of the ten worst films of 2011, saying "Ryan Reynolds and Jason Bateman have skill, charm, timing – everything but the right script."[13]